Radiotracer imaging and therapy has been a key tool for the management of many endocrine tumors, including thyroid cancer and pheochromocytoma. However, for both thyroid cancer and pheochromocytoma, more specific biochemical imaging approaches are needed to better localize these tumors and to direct treatment. We will investigate new PET based imaging techniques for these two tumor types. Radioiodine (131 I-iodide) is the mainstay of thyroid cancer therapy. However, up to 20% of patients have thyroid cancers that become refractory to 131 I, and these patients succumb to their disease. The ultimate goal is to cure thyroid cancer in these patients. We will develop approaches to characterize iodine kinetics in the tumors of individual patients using a combination of in vivo functional imaging and in vitro analysis of regulators of iodine transport, organification and effiux. This approach will be used to determine the defects in individuals with iodine-refractory thyroid cancer and to select approaches for improving the response to radioiodine. Dynamic 124 I-iodide PET after intravenous injection will be used to measure the kinetics of iodine delivery and retention by tumors, while simultaneous [15 O]-water imaging will be performed to evaluate tumor blood flow. FDG-PET imaging will be used to localize tumors and to provide information regarding metabolic activity and tumor behavior. Imaging parameters will be compared to in vitro analysis of tumor expression of features important in iodine uptake and retention. After validation, the method will be used to test whether specific therapeutic agents correct defects in iodine retention and improve 131 I therapy. In the case of pheochromocytomas, better localization and staging techniques are needed for planning surgical approach and post-surgical monitoring. 11 C-Metahydroxyephedrine (mHED), a norepinephrine analog, will be investigated as a radiotracer to provide superior image sensitivity and specificity over current approaches, including CT, MRI, and MIBG scintigraphy. The combination of mHED and FDG PET will be tested as an approach to detect pheochromocytoma with a broad range of biologic behavior. The sensitivity and specificity of mHED/FDG PET for localizing and staging pheochromocytoma will be tested, and imaging results will be correlated with biochemical analysis, surgical staging, pathological diagnosis and clinical outcome. These studies are anticipated to improve diagnosis, staging, and treatment selection for patients with thyroid cancer and pheochromocytoma and lead to new clinical applications of PET to endocrine neoplasia.